New molecular editing strategy empowers chemists to create novel drug candidates

By Nick Paul Taylor, The Science Advisory Board contributing writer

August 10, 2022 -- A new unified late-stage “molecular editing” strategy to directly modify bicyclic aza-arenes could enable chemists to synthesize a more diverse range of drug candidates.

In a study published August 9 in the journal Nature, chemists from Scripps Research and the University of California, Los Angeles (UCLA) describe helper molecules that enable the selective modification of multiple carbon atoms on bicyclic aza-arenes, a class of compounds commonly used to build drug molecules.

The helper molecules, coupled to previously reported complementary methods, could give chemists access to diverse chemical space, thereby facilitating the design of drug molecules that were previously impossible to create.

Organic synthesis, the building of organic molecules using laboratory chemistry techniques, creates some challenges for chemists. Synthetic chemists have wanted the ability to modify multiple carbon atoms, in any order, on molecules to simplify the construction of new molecules. However, at the molecular scale the interactions of atoms are governed by complex forces and chemists have struggled to come up with reactions that directly modify one specific atom without affecting other, practically identical atoms.

The new methods developed by the team at Scripps and UCLA show selective modification of multiple carbon atoms is possible, albeit only in the context of carbon atoms bound to simple hydrogen atoms at various sites on bicyclic aza-arenes. By modifying the carbon-hydrogen functionalization approach, which entails replacing hydrogen atoms with more complex sets of atoms, the researchers were able to direct the changes to desired sites.

"These new methods effectively give chemists a unified, practical, late-stage 'molecular editing' toolkit for modifying bicyclic aza-arenes at desired sites in any desired order -- greatly expanding the diversity of drugs and other useful molecules that could be built from these popular starting compounds," study co-leader Jin-Quan Yu, PhD, the Bristol Myers Squibb Endowed Chair in Chemistry at Scripps, said in a statement.

Directing templates, which serve as helper molecules, facilitate the changes by reversibly anchoring to the starting molecule and directing the functionalization. The directing templates thereby facilitate the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally-similar positions (C3 versus C7) on bicyclic aza-arenes.

The researchers achieved the breakthrough through the "careful modulation of distance, geometry, and previously unconsidered chirality in template design." Rather than direct functionalization based on the traditional electronic criteria, the chemists focused on the distance and geometry of the path to the target. The team is now working to expand the approach to other classes of starting compounds.

New machine-learning approach promises to speed drug design
A new approach to machine learning outperformed current machine-learning methods in drug design, demonstrating its potential in speeding up the drug discovery...
I-Mab collaborates on new immuno-oncology drug molecules
I-Mab has established two new collaborations with Complix and Affinity Biopharmaceutical to grow and develop its immuno-oncology pipeline.
New chemistry technique builds more precise nanoparticles
New research published in Nature Communications on November 27th demonstrates a new chemical technique that provides researchers enhanced control...

Copyright © 2022 scienceboard.net


Conferences
BioProcess International (BPI) Conference
September 27-30
Boston, Massachusetts United States
Laboratory Products Association Annual Meeting
October 1-4
Scottsdale, Arizona United States
Cell & Gene Meeting on the Mesa
October 11-13
Carlsbad, California United States
IDWeek 2022
October 19-23
District of Columbia United States
Connect
Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter